Novel dopamine uptake inhibitors are being developed to characterize the relationship between binding at the dopamine transporter, inhibition of dopamine reuptake and psychomotor stimulant behavior. Benztropine (BZT) is a dopamine uptake inhibitor, equipotent to cocaine, that exhibits CNS stimulant activity but is not reinforcing in animal models or humans. We have undertaken several synthetic strategies toward the preparation of novel BZT analogs with numerous electronically and sterically differing substituents on one or both of the phenyl rings, substitution of the 3-alpha-diphenyl ether with a b-diphenyl ether ring system or with other aryl substituents, and with various N-substituents. Further, synthetic studies directed toward potential irreversible and radiolabeled ligands will provide important research tools and may result in the discovery of a novel PET ligand, based on these compounds. Results of radiolabeled binding studies demonstrate Ki values ranging from approximately 10 to 13,000 nM. Molecular modeling studies have been initiated in which a model for optimal binding to the dopamine transporter has been derived. None of these compounds bind with high affinity to the norepinephrine or serotonin transporters and thus represent a unique class of selective dopamine transporter ligands. Structure-activity relationships demonstrate optimal binding affinity at the dopamine transporter is achieved with the following structural features: 1) the diphenyl ether must remain intact and in the alpha- stereochemistry; 2) F- or Cl-groups at the meta or para positions of one or both phenyl rings result in compounds with highest binding affinities and selectivites, with the 4',4"-di-F substitution being optimal; 3) Replacement of the N-methyl group with a butyl or benzyl substituent allows retention of high affinity at the dopamine transporter but significantly lowers binding affinities at muscarinic receptors; 4) substitution at the 2-position is unnecessary. These structure-activity relationships differ significantly from cocaine and its analogs and suggest that these classes of drugs may be interacting at a different binding domain on the dopamine transporter protein which may be responsible for their distinct pharmacological profiles. The reinforcing properties of cocaine and other psychomotor stimulants has been attributed to their inhibition of dopamine uptake. Behavioral evaluation of the BZT analogs demonstrates remarkably different profiles from other dopamine uptake inhibitors by demonstrating potent dopamine uptake inhibition but being devoid of a cocaine-like profile in animal models of psychomotor stimulant abuse. Cocaine interaction studies are underway. These compounds may provide leads for the development of a cocaine-abuse therapeutic which would decrease the prevalence of cocaine abuse and thereby curtail the transmission of HIV infection.